Spinal Muscular AtrophyPhase 2NCT01839656
A Study to Assess the Efficacy, Safety and Pharmacokinetics of Nusinersen (ISIS 396443) in Infants With Spinal Muscular Atrophy (SMA)
A Phase 2 study testing nusinersen in people with Spinal Muscular Atrophy, run by Biogen at 4 sites in 2 countries.
Trial summary
The primary objective is to examine the clinical efficacy of multiple doses of nusinersen (ISIS 396443) administered intrathecally to participants with Infantile-Onset Spinal Muscular Atrophy (SMA). Read more about this study
- Who is it for?
- Ages 21 to 210 days
- Conditions the study is for
- Spinal Muscular Atrophy
- What is being tested?
- nusinersen
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 21 participants
- Where
- 4 sitesin 2 countries
- Study dates
- 8 May 2013to 21 Aug 2017
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 21 to 210 days
- All sexes
- No healthy volunteers
- Child
Who may be able to join
- Genetic documentation of 5q SMA (homozygous gene deletion or mutation)
- Onset of clinical signs and symptoms consistent with SMA at ≥ 21 days and <6 months (180 days) of age
- At study entry, receiving adequate nutrition and hydration (with or without gastrostomy), in the opinion of the Site Investigator
- Body weight >5th percentile for age using Center of Disease Control and Prevention (CDC) guidelines
- Medical care meets and is expected to continue to meet guidelines set out in the Consensus Statement for Standard of Care in SMA (Wang et al. 2007), in the opinion of the Site Investigator
- Gestational age of 35 to 42 weeks and gestation body weight ≥2 kg
- Reside within approximately 9 hours ground-travel distance from a participating study center for the duration of the study. Residence >2 hours ground-travel distance from a study center must obtain clearance from the Site Investigator and the study Medical Monitor
- Able to complete all study procedures, measurements and visits and parent or guardian/participant has adequately supportive psychosocial circumstances, in the opinion of the Site Investigator
Who cannot join
- Hypoxemia (O2 saturation awake <96% or O2 saturation asleep <96%, without ventilation support)
- Presence of an untreated or inadequately treated active infection requiring systemic antiviral or antimicrobial therapy at any time during the screening period
- History of brain or spinal cord disease that would interfere with the lumbar puncture (LP) procedures, CSF circulation, or safety assessments
- Presence of an implanted shunt for the drainage of cerebrospinal fluid (CSF) or an implanted central nervous system (CNS) catheter
- History of bacterial meningitis
- Clinically significant abnormalities in hematology or clinical chemistry parameters, as assessed by the Site Investigator, at screening that would render the participant unsuitable for inclusion
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- Treatment with another investigational drug (e.g., albuterol, riluzole, carnitine, creatine, sodium phenylbutyrate, salbutamol, valproate, hydroxyurea etc), biological agent, or device within 90 days prior to enrollment or anytime during the study. Any history of gene therapy or cell transplantation
- The participants parent(s) or legal guardian(s) is unable to understand the nature, scope, and possible consequences of the study, or does not agree to comply with the protocol defined schedule of assessments
- Ongoing medical condition that according to the Site Investigator would interfere with the conduct and assessments of the study. Examples are medical disability other than SMA that would interfere with the assessment of safety or would compromise the ability of the participant to undergo study procedures
- NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.
Trial locations and contacts
4 sites in 2 countries.
4 sites in 2 countries
United States3 sites
Columbia University Medical Center
New York, New York, 10032
Nemours Children's Hospital
Orlando, Florida, 32827
Stanford University Medical Center
Stanford, California, 94305
Canada1 site
The Hospital for Sick Children (SickKids)
Toronto, Ontario, M5G 1X8
About this study
Official title: A Study to Assess the Efficacy, Safety, Tolerability, and Pharmacokinetics of Multiple Doses of ISIS 396443 Delivered Intrathecally to Patients With Infantile-Onset Spinal Muscular Atrophy
The primary objective is to examine the clinical efficacy of multiple doses of nusinersen (ISIS 396443) administered intrathecally to participants with Infantile-Onset Spinal Muscular Atrophy (SMA). The secondary objectives are to examine the safety and tolerability of multiple doses of nusinersen administered intrathecally to participants with infantile-onset SMA and to examine the cerebral spinal fluid (CSF) and plasma Pharmacokinetics (PK) of multiple doses of nusinersen administered intrathecally to participants with infantile-onset SMA.
Read the detailed description
This study was conducted and the protocol was registered by Ionis Pharmaceuticals, Inc.. In August 2016, sponsorship of the trial was transferred to Biogen.
- Conditions
- Spinal Muscular Atrophy
- Being tested
- nusinersen
- Keywords
- Spinal Muscular Atrophy, SMA, SMN, SMNRx, ISIS-SMNRx, ISIS 396443, IONIS-SMNRx, Spinraza, Nusinersen
- Medical subject headings
- Muscular Atrophy, Spinal
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
nusinersenDrug
Also called ISIS 396443, Spinraza, BIIB058, IONIS SMN Rx
Administered by intrathecal (IT) injection
| Study group | Role | What they receive |
|---|---|---|
| Nusinersen 6 mg | Experimental | Not described Receives: Drug: nusinersen |
| Nusinersen 12 mg | Experimental | Not described Receives: Drug: nusinersen |
What is being measured
The primary outcome is the main question the study is designed to answer.
Percent of Participants Who Achieved Improvement in Motor Milestones as Assessed by Section 2 of the HINE at the Last Visit
Section 2 of HINE consists of 8 independent milestone categories. Within each of these categories, participants can progress from complete absence of a motor ability (the lowest level in each category) through multiple milestones (2 to 4 levels in each category) to the highest level within the category. Overall, there are a total of 26 milestones that can be achieved across the 8 categories. Improvement was defined as any of the following: 1. An increase from baseline of 2 milestones or more, or the achievement of pincer grasp in the voluntary grasp category 2. An increase from baseline of 2 milestones or more, or achievement of touching toes in the ability to kick category 3. An increase from baseline of 1 milestone or more in any of the remaining 6 categories: head control, rolling, sitting, crawling, standing, or walking.
Measured: Day 1352 or Early Termination
Secondary outcomes (8)
Event-free Survival at the End of Study
Event-free survival was defined as the percent of participants who were alive and did not require permanent ventilatory support (defined as tracheostomy or the need for ≥16 hours ventilation/day continuously for at least 2 weeks in the absence of an acute reversible illness) Event-free survival was estimated using Kaplan-Meier methodology.
Measured: Up to Day 1638
Percent of Participants With Improved Motor Function at the Last Visit as Assessed by the CHOP-INTEND Motor Function Scale
The CHOP-INTEND test includes 16 items structured to move from easiest to hardest with the grading including gravity eliminated (lower scores) to antigravity movements (higher scores). All item scores range from 0 (worst) to 4 (best). Total scores range from 0 to 64, with higher scores indicating better movement functioning. Improvement was defined as an increase in total CHOP INTEND score ≥4 points from baseline as of the last study visit.
Measured: Day 1352 or Early Termination
Change in Neuromuscular Electrophysiology at the Last Visit as Assessed by the Change From Baseline in CMAP Amplitude
CMAP is an electrophysiological technique that can be used to determine the approximate number of motor neurons in a muscle or group of muscles. A positive change from Baseline indicates that the number of motor neurons increased.
Measured: Baseline, Day 1072
Number of Participants Experiencing Adverse Events (AEs) and/or Serious Adverse Events (SAEs)
AE: any unfavorable and unintended sign, symptom, or disease temporally associated with the study or use of investigational drug product, whether or not the AE is considered related to the investigational drug product. SAE: any AE that in the view of either the Investigator or Sponsor, meets any of the following criteria: results in death; is life threatening: that is, poses an immediate risk of death at the time of the event; requires in-patient hospitalization or prolongation of existing hospitalization; results in a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions; results in congenital anomaly or birth defect in the offspring of the subject (whether male or female); is an important medical event in the opinion of the Investigator or Sponsor.
Measured: Up to Day 1352
Concentration of Nusinersen in Cerebrospinal Fluid (CSF)
The concentration of nusinersen in CSF was measured by using standard laboratory assays.
Measured: Day 1135 (Predose)
PK Parameters of Nusinersen in Plasma: Maximum Concentration (Cmax)
Cmax is the maximum observed concentration of study drug in plasma.
Measured: Day 1 (Predose and 1, 2, and 4 hours [hr] Postdose) and Day 2 (24 hr Postdose )
PK Parameters of Nusinersen in Plasma: Time to Reach Cmax (Tmax)
Tmax is the time at which Cmax occurs.
Measured: Day 1 (Predose and 1, 2, and 4 hours [hr] Postdose) and Day 2 (24 hr Postdose )
PK Parameters of Nusinersen in Plasma: Area Under the Plasma Concentrations Time Curve From the Time of the IT Dose to Four Hours After Dosing (AUC0-4)
AUC is area under the plasma concentration-time curve from zero time (Predose) to 4 hours after IT administration of study drug. AUC was determined by using the linear trapezoidal rule.
Measured: Day 1 (Predose and 1, 2, and 4 hours [hr] Postdose) and Day 2 (24 hr Postdose )
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted25 Apr 2013 (estimated)
- Study start8 May 2013
- Primary completion21 Aug 2017
- Study completion21 Aug 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Spinal Muscular AtrophyStudies of the same condition, open and under way.
- More trials run by BiogenThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 21 participants (actual)
Sponsor and investigators
- Lead sponsor
- Biogen
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Medical Director, Study director, Biogen
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01839656
- Sponsor's protocol ID
- ISIS 396443-CS3A
- Other IDs
- 2017-000621-12, 2017
- Status last verified
- Feb 2021
- First submitted
- 22 Apr 2013
- Last updated
- 17 Feb 2021
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Expanded access
- Available
Publications
Finkel RS, Chiriboga CA, Vajsar J, Day JW, Montes J, De Vivo DC, Bishop KM, Foster R, Liu Y, Ramirez-Schrempp D, Schneider E, Bennett CF, Wong J, Farwell W. Treatment of infantile-onset spinal muscular atrophy with nusinersen: final report of a phase 2, open-label, multicentre, dose-escalation study. Lancet Child Adolesc Health. 2021 Jul;5(7):491-500. doi: 10.1016/S2352-4642(21)00100-0. Epub 2021 Jun 3.
PubMed 34089650Darras BT, Farrar MA, Mercuri E, Finkel RS, Foster R, Hughes SG, Bhan I, Farwell W, Gheuens S. An Integrated Safety Analysis of Infants and Children with Symptomatic Spinal Muscular Atrophy (SMA) Treated with Nusinersen in Seven Clinical Trials. CNS Drugs. 2019 Sep;33(9):919-932. doi: 10.1007/s40263-019-00656-w.
PubMed 31420846Finkel RS, Chiriboga CA, Vajsar J, Day JW, Montes J, De Vivo DC, Yamashita M, Rigo F, Hung G, Schneider E, Norris DA, Xia S, Bennett CF, Bishop KM. Treatment of infantile-onset spinal muscular atrophy with nusinersen: a phase 2, open-label, dose-escalation study. Lancet. 2016 Dec 17;388(10063):3017-3026. doi: 10.1016/S0140-6736(16)31408-8. Epub 2016 Dec 7.
PubMed 27939059
Study at a glance
From the registry record, last updated by the sponsor on 17 Feb 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Study to Assess the Efficacy, Safety, Tolerability, and Pharmacokinetics of Multiple Doses of ISIS 396443 Delivered Intrathecally to Patients With Infantile-Onset Spinal Muscular Atrophy
- ClinicalTrials.gov ID
- NCT01839656
- Acronym / sponsor ID
- ISIS 396443-CS3A
- Conditions
- Spinal Muscular Atrophy
- Keywords
- Spinal Muscular Atrophy, SMA, SMN, SMNRx, ISIS-SMNRx, ISIS 396443, IONIS-SMNRx, Spinraza
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 21 participants (actual)
- Lead sponsor
- BiogenIndustry (pharma, biotech, devices)
- Study start
- 8 May 2013 (actual)
- Primary completion
- 21 Aug 2017 (actual)
- Study completion
- 21 Aug 2017 (actual)
- First posted
- 25 Apr 2013 (estimated)
- Results
- Posted 30 Oct 2018
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The primary objective is to examine the clinical efficacy of multiple doses of nusinersen (ISIS 396443) administered intrathecally to participants with Infantile-Onset Spinal Muscular Atrophy (SMA). The secondary objectives are to examine the safety and tolerability of multiple doses of nusinersen administered intrathecally to participants with infantile-onset SMA and to examine the cerebral spinal fluid (CSF) and plasma Pharmacokinetics (PK) of multiple doses of nusinersen administered intrathecally to participants with infantile-onset SMA.
Detailed description
This study was conducted and the protocol was registered by Ionis Pharmaceuticals, Inc.. In August 2016, sponsorship of the trial was transferred to Biogen.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Nusinersen 6 mg | Experimental | Drug: nusinersen |
| Nusinersen 12 mg | Experimental | Drug: nusinersen |
Who may qualify
- Ages
- 21 to 210 days
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (8 listed)
- Genetic documentation of 5q SMA (homozygous gene deletion or mutation)
- Onset of clinical signs and symptoms consistent with SMA at ≥ 21 days and <6 months (180 days) of age
- At study entry, receiving adequate nutrition and hydration (with or without gastrostomy), in the opinion of the Site Investigator
- Body weight >5th percentile for age using Center of Disease Control and Prevention (CDC) guidelines
- Medical care meets and is expected to continue to meet guidelines set out in the Consensus Statement for Standard of Care in SMA (Wang et al. 2007), in the opinion of the Site Investigator
Key exclusion criteria (10 listed)
- Hypoxemia (O2 saturation awake <96% or O2 saturation asleep <96%, without ventilation support)
- Presence of an untreated or inadequately treated active infection requiring systemic antiviral or antimicrobial therapy at any time during the screening period
- History of brain or spinal cord disease that would interfere with the lumbar puncture (LP) procedures, CSF circulation, or safety assessments
- Presence of an implanted shunt for the drainage of cerebrospinal fluid (CSF) or an implanted central nervous system (CNS) catheter
- History of bacterial meningitis
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| nusinersenAlso: ISIS 396443, Spinraza, BIIB058, IONIS SMN RxAdministered by intrathecal (IT) injection | Drug | Nusinersen 12 mg, Nusinersen 6 mg |
Primary outcome
Percent of Participants Who Achieved Improvement in Motor Milestones as Assessed by Section 2 of the HINE at the Last Visit
Time frame: Day 1352 or Early Termination
Section 2 of HINE consists of 8 independent milestone categories. Within each of these categories, participants can progress from complete absence of a motor ability (the lowest level in each category) through multiple milestones (2 to 4 levels in each category) to the highest level within the category. Overall, there are a total of 26 milestones that can be achieved across the 8 categories. Improvement was defined as any of the following: 1. An increase from baseline of 2 milestones or more, or the achievement of pincer grasp in the voluntary grasp category 2. An increase from baseline of 2 milestones or more, or achievement of touching toes in the ability to kick category 3. An increase from baseline of 1 milestone or more in any of the remaining 6 categories: head control, rolling, sitting, crawling, standing, or walking.
8 secondary outcomes
Event-free Survival at the End of Study
Time frame: Up to Day 1638
Percent of Participants With Improved Motor Function at the Last Visit as Assessed by the CHOP-INTEND Motor Function Scale
Time frame: Day 1352 or Early Termination
Change in Neuromuscular Electrophysiology at the Last Visit as Assessed by the Change From Baseline in CMAP Amplitude
Time frame: Baseline, Day 1072
Number of Participants Experiencing Adverse Events (AEs) and/or Serious Adverse Events (SAEs)
Time frame: Up to Day 1352
Concentration of Nusinersen in Cerebrospinal Fluid (CSF)
Time frame: Day 1135 (Predose)
PK Parameters of Nusinersen in Plasma: Maximum Concentration (Cmax)
Time frame: Day 1 (Predose and 1, 2, and 4 hours [hr] Postdose) and Day 2 (24 hr Postdose )
PK Parameters of Nusinersen in Plasma: Time to Reach Cmax (Tmax)
Time frame: Day 1 (Predose and 1, 2, and 4 hours [hr] Postdose) and Day 2 (24 hr Postdose )
PK Parameters of Nusinersen in Plasma: Area Under the Plasma Concentrations Time Curve From the Time of the IT Dose to Four Hours After Dosing (AUC0-4)
Time frame: Day 1 (Predose and 1, 2, and 4 hours [hr] Postdose) and Day 2 (24 hr Postdose )
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 17 Feb 2021.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 34089650Finkel RS, Chiriboga CA, Vajsar J, Day JW, Montes J, De Vivo DC, Bishop KM, Foster R, Liu Y, Ramirez-Schrempp D, Schneider E, Bennett CF, Wong J, Farwell W. Treatment of infantile-onset spinal muscular atrophy with nusinersen: final report of a phase 2, open-label, multicentre, dose-escalation study. Lancet Child Adolesc Health. 2021 Jul;5(7):491-500. doi: 10.1016/S2352-4642(21)00100-0. Epub 2021 Jun 3.
- Derived from this study: PubMed 31420846Darras BT, Farrar MA, Mercuri E, Finkel RS, Foster R, Hughes SG, Bhan I, Farwell W, Gheuens S. An Integrated Safety Analysis of Infants and Children with Symptomatic Spinal Muscular Atrophy (SMA) Treated with Nusinersen in Seven Clinical Trials. CNS Drugs. 2019 Sep;33(9):919-932. doi: 10.1007/s40263-019-00656-w.
- Derived from this study: PubMed 27939059Finkel RS, Chiriboga CA, Vajsar J, Day JW, Montes J, De Vivo DC, Yamashita M, Rigo F, Hung G, Schneider E, Norris DA, Xia S, Bennett CF, Bishop KM. Treatment of infantile-onset spinal muscular atrophy with nusinersen: a phase 2, open-label, dose-escalation study. Lancet. 2016 Dec 17;388(10063):3017-3026. doi: 10.1016/S0140-6736(16)31408-8. Epub 2016 Dec 7.
- Cure SMALink provided by the sponsor.
- Muscular Dystrophy AssociationLink provided by the sponsor.
- National Organization for Rare DiseasesLink provided by the sponsor.
- Clinical Study Report (CSR) Synopsis - a results summaryLink provided by the sponsor.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Medical Director study director
Biogen
4 sites in 2 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing nusinersen in people with Spinal Muscular Atrophy, run by Biogen at 4 sites in 2 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 17 Feb 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 4 sites in United States, Canada. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 30 Oct 2018). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Percent of Participants Who Achieved Improvement in Motor Milestones as Assessed by Section 2 of the HINE at the Last Visit (time frame: Day 1352 or Early Termination). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01839656, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 17 Feb 2021.